CN106187886B - A method of preparing high-purity Bosutinib monohydrate - Google Patents
A method of preparing high-purity Bosutinib monohydrate Download PDFInfo
- Publication number
- CN106187886B CN106187886B CN201610529036.8A CN201610529036A CN106187886B CN 106187886 B CN106187886 B CN 106187886B CN 201610529036 A CN201610529036 A CN 201610529036A CN 106187886 B CN106187886 B CN 106187886B
- Authority
- CN
- China
- Prior art keywords
- bosutinib
- purity
- water
- alkyl halide
- monohydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 34
- 229960004152 bosutinib monohydrate Drugs 0.000 title abstract description 30
- 239000002145 L01XE14 - Bosutinib Substances 0.000 claims abstract description 40
- 229960003736 bosutinib Drugs 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 238000001035 drying Methods 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 150000004682 monohydrates Chemical class 0.000 claims description 15
- 150000001350 alkyl halides Chemical class 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- -1 2,4- bis- Chloro-5-methoxyl anilino- Chemical class 0.000 claims description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 230000036571 hydration Effects 0.000 abstract description 2
- 238000006703 hydration reaction Methods 0.000 abstract description 2
- BXPOSPOKHGNMEP-UHFFFAOYSA-N bosutinib hydrate Chemical compound O.C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl BXPOSPOKHGNMEP-UHFFFAOYSA-N 0.000 description 25
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000010606 normalization Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000003714 granulocyte Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention discloses a kind of methods for preparing high-purity Bosutinib monohydrate, comprising the following steps: Bosutinib crude product is dissolved in water-alkyl halide mixed liquor, stirring and crystallizing, filtering, drying, obtains the Bosutinib monohydrate of high-purity.The present invention turns the brilliant Bosutinib monohydrate that can rapidly and efficiently obtain high-purity by control Crystallization method, without recrystallizing and heating hydration.The method of preparation high-purity Bosutinib monohydrate of the invention, preparation process is simple, convenient, time saving and energy saving, consumes energy low, saves production cost, with short production cycle, and the purity is high of obtained product has important economic significance up to 99.6% or more.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a method of prepare high-purity Bosutinib monohydrate.
Background technique
Bosutinib (Bosutinib) also known as bosutinib, Bosutinib, pool, which relaxes, replaces Buddhist nun, title are as follows: 4- [(2,
The chloro- 5- methoxyphenyl of 4- bis-) amino]-6- methoxyl group-7- [3- (4- methyl-1-piperazine) propoxyl group]-3- quinolinecarbonitriles, knot
Structure formula is as follows；Molecular formula: C26H29Cl2N5O3, molecular weight: 530.45.
Bosutinib was developed by Wyeth Pharmaceuticals, the U.S. (Wyeth Pharmaceuticals), on September 4th, 2012
FDA approval is for chronic, acceleration or rapid change period Ph+CML adult patients.Most of CML patient is with referred to as Philadelphia chromosome
Gene mutation, this cause marrow generate tyrosine kinase.It is unsound white thin that this enzyme triggering marrow generates excessive deformity
Born of the same parents, that is, granulocyte.Granulocyte can be to anti-infective.Bosutinib is by blocking tyrosine kinase that marrow is stimulated to accelerate to generate deformity
The signal of unsound granulocyte and play a role.
Bosutinib is a kind of oral kinase inhibitors drug that need to be only administered once daily, which is SRC and BCR
ABL double inhibitor, by inhibiting Abl and Src signal transduction pathway to contain the growth of tumour cell.
Chinese patent application CN101248047A is related to Bosutinib novel crystal forms (I type) and preparation method thereof, method packet
It includes with the anhydrous 4- of hot water treatment [(the chloro- 5- methoxyphenyl of 2,4- bis-) amino]-6- methoxyl group-7- [3- (4- methyl-1-piperazine)
Propoxyl group] -3- quinolinecarbonitriles the step of.
Document [Xiao JY, Guan HX, Xu S, etal.Synthesis of bosutinib from 3-methoxy-
4-hydroxybenzoic acid [J] .Molecules, 2010,15 (6): 4261-4266.] involved in Bosutinib synthesis
Method.Document WO2004078709A2, CN101792416.B are also the patent of the synthetic method about Bosutinib.
The obtained Bosutinib purity of synthetic method in above-mentioned document is not high, needs column chromatographic purifying or quick column pure
Change, products obtained therefrom purity is not high, and appearance is poor, needs to carry out recrystallization purifying again.It is additionally useful for needing to carry out when preparation preparation
The crystal form of monohydrate is converted, and needs for product to be heated to 90 DEG C or more in water, heating, cooling, when energy charge.
Summary of the invention
In view of the deficiencies of the prior art, a kind of method preparing high-purity Bosutinib monohydrate is provided, the party is passed through
Method products obtained therefrom purity is high, and it is few to consume energy.
The invention adopts the following technical scheme:
A method of preparing high-purity Bosutinib monohydrate, comprising the following steps: be dissolved in Bosutinib crude product
In water-alkyl halide mixed liquor, stirring and crystallizing, filtering, drying obtain the Bosutinib monohydrate of high-purity.
Preferably, the Bosutinib crude product can be obtained according to prior art preparations such as CN101792416A.
Bosutinib crude product of the invention refers to having obtained object Bosutinib but not purified containing impurity
Mixture, or after purification, but still the mixture containing impurity.Bosutinib crude product of the invention can be by existing
A variety of methods in technology are prepared, for example, Bosutinib crude product can be to be prepared into embodiment 5 in CN105503719A
The white solid arrived；Alternatively, using the technical solution provided in the embodiment of the present invention.
Further preferred are as follows: the reaction solution containing Bosutinib is evaporated, the Bai Shu containing impurity can be obtained
For Buddhist nun's crude product；Wherein, the reaction solution containing Bosutinib is that preparation is normal in the process for prepare in the prior art Bosutinib
What rule obtained.
High-purity in the Bosutinib monohydrate of high-purity of the present invention refers to that purity is equal to greater than 90%, or
Person be equal to be greater than 95%, perhaps be equal to greater than 98% or be equal to be greater than 99%, preferably be equal to 99.61%, 99.68%,
99.69%, 99.78%, 99.87% etc..
Bosutinib crude product is dissolved in wherein one of the specific method in water-alkyl halide mixed liquor in following methods
Kind:
Stirring and dissolving in alkyl halide is added in Bosutinib after being evaporated (the i.e. described Bosutinib crude product), is then added
Water, stirring and crystallizing, filtering, drying obtain the Bosutinib sulfuric monohydrate of high-purity.
Alternatively, water is added in the Bosutinib after being evaporated (the i.e. described Bosutinib crude product), then it is neutralized, then
Alkyl halide is added, stirring and crystallizing, filtering, drying obtain the Bosutinib sulfuric monohydrate of high-purity.
The concrete mode of the neutralisation treatment are as follows: lye (such as sodium hydroxide solution) is added and neutralizes, until pH is 7~9.
Preferably, it is washed, is washed using corresponding alkyl halide after filtration.
Preferably, in the mixed liquor of the water-alkyl halide, the volume ratio of water and alkyl halide is 10:1~1:10, further
Preferably 5:1~1:5, most preferably 1:1.Purity can be prepared more using water-alkyl halide mixed liquor of this ratio
High Bosutinib sulfuric monohydrate, and preparation efficiency is higher.
Preferably, the Bosutinib monohydrate additive amount ratio of the mixed liquor of the water-alkyl halide and gained high-purity
For (5~50) ml:1g, further preferably (10~40) ml:1g.Using water-alkyl halide mixed liquor of this volume ratio, so that
The preparation efficiency of Bosutinib monohydrate is higher, energy consumption is less.
Preferably, the alkyl halide is liquid alkyl halide, is further selected from methylene chloride, chloroform, methylene bromide, two
Any one in chloroethanes, Bromofume or other liquid alkyl halides.
Preferably, the temperature of the stirring and crystallizing is 0~50 DEG C, is further preferably 25~40 DEG C, this stirring and crystallizing
Temperature makes the stirring and crystallizing time used shorter, precipitation Bosutinib monohydrate that can be more efficient.
Preferably, the time of the stirring and crystallizing is 1~48h, further preferably 6~for 24 hours.
The beneficial effects of the present invention are:
When being easily soluble in the Bosutinib of alkyl halide and being stirred in water-alkyl halide mixed liquor, it can be formed insoluble in should
The monohydrate of mixed liquor and be precipitated, the Bosutinib monohydrate product of high-purity can be obtained by being filtered, washed, drying,
The impurity that synthesis process generates stays in alkyl halide and water, so that the Bosutinib monohydrate of high-purity be prepared.
The present invention by control Crystallization method, without recrystallize and heat hydration turn crystalline substance can rapidly and efficiently obtain it is high-purity
The Bosutinib monohydrate of degree.
The method of preparation high-purity Bosutinib monohydrate of the invention, preparation process is simple, convenient, time saving and energy saving,
It consumes energy low, saves production cost, it is with short production cycle, and the purity is high of obtained product has important up to 99.6% or more
Economic significance.
Specific embodiment
Below with reference to embodiment, the present invention is further described.
Instrument involved in following embodiments, reagent, material etc. are unless otherwise noted existing in the prior art
Conventional instrument, reagent, material etc., can be obtained by regular commercial sources.Experimental method involved in following embodiments, inspection
Survey method etc. is unless otherwise noted existing routine experiment method in the prior art, detection method etc..Synthesis uncle, which is relaxed, to be replaced
The method of Buddhist nun is not limited only to cited method.
Embodiment 1 prepares high-purity Bosutinib monohydrate
Method is as follows: by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (the chloro- 5- methoxybenzene amido of 2,4- bis-) -3- cyano
Reaction solution is concentrated under reduced pressure after 80 DEG C are reacted 12 hours in quinoline (A) 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml
To dry, addition 50ml chloroform stirring and dissolving, 50ml water is added, 30~40 DEG C of heat preservations are simultaneously stirred to react 6 hours, filter,
Chloroform washs filter cake, and drying obtains Bosutinib monohydrate white crystalline powder 3.3g, and HPLC measures (area normalization
Method): 99.87%, X-ray, TG, DSC are measured as monohydrate.
Reaction equation are as follows:
Embodiment 2 prepares high-purity Bosutinib monohydrate
Method is as follows: by 2- itrile group-N- (the chloro- 5- methoxyphenyl of 2,4- bis-) -3- [4- methoxyl group -3- [3- (4- methyl
Piperazine -1- base)-propoxyl group]-phenyl amino]-acrylamide (B) 5.5g, acetonitrile 100ml addition reaction flask, it is heated to reflux lower drop
Add phosphorus oxychloride 20g, be added dropwise, be heated to reflux 40 hours, cooling, reaction solution is concentrated to dryness, and 30ml water is added, with full
Being neutralized to pH with sodium hydroxide solution is 9, and 50ml chloroform is added, is stirred at room temperature 24 hours, filters, chloroform washing filter
Cake, drying obtain Bosutinib monohydrate white crystalline powder 2.9g, and HPLC measures (area normalization method): 99.69%, X-
Ray, TG, DSC are measured as monohydrate.
Reaction equation are as follows:
Embodiment 3 prepares high-purity Bosutinib monohydrate
Method is as follows: by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (the chloro- 5- methoxybenzene amido of 2,4- bis-) -3- cyano
Reaction solution is concentrated under reduced pressure after 80 DEG C are reacted 12 hours in quinoline (A) 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml
To dry, addition 60ml methylene chloride stirring and dissolving, 60ml water is added, 5~10 DEG C of heat preservations are simultaneously stirred to react 24 hours, filter,
Methylene chloride washs filter cake, and drying obtains Bosutinib monohydrate white crystalline powder 3.1g, and HPLC measures (area normalization
Method): 99.68%., X-ray, TG, DSC are measured as monohydrate.
Embodiment 4 prepares high-purity Bosutinib monohydrate
Method is as follows: by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (the chloro- 5- methoxybenzene amido of 2,4- bis-) -3- cyano
Reaction solution is concentrated under reduced pressure after 80 DEG C are reacted 12 hours in quinoline (A) 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml
To dry, addition 50ml methylene bromide stirring and dissolving, 50ml water is added, 25~30 DEG C of heat preservations are simultaneously stirred to react 20 hours, filter,
Methylene bromide washs filter cake, and drying obtains Bosutinib monohydrate white crystalline powder 2.8g, and HPLC measures (area normalization
Method): 99.61%, X-ray, TG, DSC are measured as monohydrate.
Embodiment 5 prepares high-purity Bosutinib monohydrate
Method is as follows: by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (the chloro- 5- methoxybenzene amido of 2,4- bis-) -3- cyano
Reaction solution is concentrated under reduced pressure after 80 DEG C are reacted 12 hours in quinoline (A) 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml
To dry, addition 60ml dichloroethanes stirring and dissolving, 60ml water is added, 20~30 DEG C of heat preservations are simultaneously stirred to react 2 hours, filter,
Dichloroethanes washs filter cake, and drying obtains Bosutinib monohydrate white crystalline powder 3.0g, and HPLC measures (area normalization
Method): 99.78%, X-ray, TG, DSC are measured as monohydrate.
Embodiment 6 prepares high-purity Bosutinib monohydrate
Method is as follows: by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (the chloro- 5- methoxybenzene amido of 2,4- bis-) -3- cyano
Reaction solution is concentrated under reduced pressure after 80 DEG C are reacted 12 hours in quinoline (A) 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml
To dry, addition 40ml Bromofume stirring and dissolving, 40ml water is added, 30~50 DEG C of heat preservations are simultaneously stirred to react 24 hours, filter,
Bromofume washs filter cake, and drying obtains Bosutinib monohydrate white crystalline powder 2.7g, and HPLC measures (area normalization
Method): 99.68%, X-ray, TG, DSC are measured as monohydrate.
By lot of experiment validation and analysis, in specific embodiment in addition to using above-mentioned halogenated alkane, other liquid
Halogenated alkane be also suitable process of the invention.
Claims (7)
1. a kind of method for preparing high-purity Bosutinib sulfuric monohydrate, characterized in that the following steps are included: by Bosutinib
Crude product is dissolved in water-alkyl halide mixed liquor, and stirring and crystallizing, filtering, drying obtain Bosutinib sulfuric monohydrate；It is described to stir
The temperature for mixing crystallization is 0~50 DEG C；The Bosutinib crude product is by 7- (3- chloropropanol oxygen radical) -6- methoxyl group -4- (2,4- bis-
Chloro-5-methoxyl anilino-) -3- chloro quinoline 4.67g, sodium iodide 1.5g and N methyl piperazine 40ml, react 12 in 80 DEG C
After hour, reaction solution is concentrated under reduced pressure and is prepared or to dry by 2- itrile group-N- (2,4- bis- chloro- 5- methoxyphenyl) -3- [4- first
Oxygroup -3- [3- (4- methylpiperazine-1-yl)-propoxyl group]-phenyl amino]-acrylamide 5.5g, acetonitrile 100ml addition reaction
Bottle, is heated to reflux lower dropwise addition phosphorus oxychloride 20g, is added dropwise, be heated to reflux 40 hours, cooling, and reaction solution is concentrated to dryness
It obtains；
The alkyl halide is any one of methylene chloride, chloroform, methylene bromide, dichloroethanes, Bromofume.
2. the method as described in claim 1, characterized in that specific step is as follows: Bosutinib crude product is added in alkyl halide
Stirring and dissolving, then adds water, and stirring and crystallizing, filtering, drying obtain Bosutinib sulfuric monohydrate.
3. the method as described in claim 1, characterized in that specific step is as follows: by Bosutinib crude product be added water, then into
Row neutralisation treatment, adds alkyl halide, and stirring and crystallizing, filtering, drying obtain Bosutinib sulfuric monohydrate.
4. method as claimed in claim 3, characterized in that the concrete mode of the neutralisation treatment are as follows: be added in lye, until pH
It is 7~9.
5. the method as described in claim 1, it is characterized in that: in the mixed liquor of the water-alkyl halide, the volume of water and alkyl halide
Than for 1:1.
6. the method as described in claim 1, it is characterized in that: the mixed liquor of the water-alkyl halide and one water of gained Bosutinib
Compound additive amount ratio is 10~40mL:1g.
7. the method as described in claim 1, it is characterized in that: the time of the stirring and crystallizing is 1~48h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610529036.8A CN106187886B (en) | 2016-07-06 | 2016-07-06 | A method of preparing high-purity Bosutinib monohydrate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610529036.8A CN106187886B (en) | 2016-07-06 | 2016-07-06 | A method of preparing high-purity Bosutinib monohydrate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106187886A CN106187886A (en) | 2016-12-07 |
| CN106187886B true CN106187886B (en) | 2019-04-16 |
Family
ID=57465591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610529036.8A Active CN106187886B (en) | 2016-07-06 | 2016-07-06 | A method of preparing high-purity Bosutinib monohydrate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106187886B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007005462A1 (en) * | 2005-07-01 | 2007-01-11 | Wyeth | Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile and methods of preparing the same |
| CN104447542A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Bosutinib monohydrate and preparation method thereof |
| CN104447541A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Bosutinib compound |
| CN105384686A (en) * | 2014-09-04 | 2016-03-09 | 连云港润众制药有限公司 | Bosutinib crystallization method |
-
2016
- 2016-07-06 CN CN201610529036.8A patent/CN106187886B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007005462A1 (en) * | 2005-07-01 | 2007-01-11 | Wyeth | Crystalline forms of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methyl-1-piperazinyl)propoxy]-3-quinolinecarb-onitrile and methods of preparing the same |
| CN104447542A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Bosutinib monohydrate and preparation method thereof |
| CN104447541A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Bosutinib compound |
| CN105384686A (en) * | 2014-09-04 | 2016-03-09 | 连云港润众制药有限公司 | Bosutinib crystallization method |
Non-Patent Citations (4)
| Title |
|---|
| A Robust, Streamlined Approach to Bosutinib Monohydrate;Gregory J. Withbroe等;《Org. Process Res. Dev.》;20120703;第17卷;500−504 |
| Demonstration of Controls To Ensure Product Quality.《Org. Process Res. Dev.》.2015,第19卷1997−2005. |
| Paul Bowles等.Confirmation of Bosutinib Structure |
| 博舒替尼合成路线图解;韩金娥等;《中国新药杂志》;20141231;第23卷(第4期);462-464 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106187886A (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106146379B (en) | A kind of synthetic method of Oxiracetam | |
| CN104860894B (en) | Method for preparing cardiotonic drug LCZ696 | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN102491918A (en) | Alanyl glutamine compound and preparation method thereof | |
| CN111548310B (en) | Levosimendan sodium crystal form and preparation method thereof | |
| CN108017561A (en) | A kind of method of refined card glutamic acid | |
| CN106222230A (en) | A kind of method of green enzymatic clarification cefaclor | |
| CN106187886B (en) | A method of preparing high-purity Bosutinib monohydrate | |
| CN105440054B (en) | A kind of technique preparing cefathiamidine | |
| CN109516991B (en) | Tofacitinib citrate crystal form compound and preparation method thereof | |
| CN108997209B (en) | Preparation method of regorafenib | |
| CN104072442B (en) | A kind of compound and preparation method thereof | |
| CN112358467B (en) | Preparation process of pyrroltinib | |
| CN103739635B (en) | A kind of purification process of mannose triflate intermediate | |
| CN102363621B (en) | Cefminox sodium hexahydrate, preparation method thereof and pharmaceutical composition containing hexahydrate | |
| CN115124506A (en) | Preparation method of medicine for digestive system | |
| CN102432532B (en) | High-purity torasemide compound | |
| CN105130997A (en) | Preparation method of copanlisib | |
| CN102887851B (en) | Compound 3,5-dimethyl-1H-pyrrole-2,4-diformaldehyde and preparation method thereof | |
| CN104725349A (en) | Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof | |
| CN110229155A (en) | A kind of preparation method of l-leucovorin calcium impurities and impurity calcium salt | |
| CN101717347B (en) | Method for preparing L-theanine by chemical method | |
| CN119751541B (en) | A kind of synthesis method of high-purity magnesium isoglycyrrhizinate | |
| CN117800947A (en) | Preparation method of nilotinib hydrochloride bulk drug impurities | |
| CN103896919A (en) | Preparation method of deuterium-substituted dabigatran etexilate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |